It is generally known that pregnant women who experience spontaneous preterm birth (PTB) begin with preterm labor (also interchangeably referred to herein as “premature labor”) and start having regular contractions that cause their cervix to start to open or thin out (called dilation and effacement) and soften before they reach about 37 weeks of gestation. If a woman delivers a baby before 37 weeks, it is typically and conventionally called a preterm birth and the baby is considered premature.
Preterm birth remains one of the most serious problems in obstetrics, with enormous impact on infants, their families, and our society. According to a recent study published by the Institute of Medicine, the incidence of preterm birth has grown 33% since 1981, and each year approximately 500,000 women deliver prematurely in the U.S. alone resulting in a $26 billion annual cost of premature birth to our nation's healthcare system. It has recently been reported that preterm births occur in 15% of pregnancies in the developed world and 12.7% of all births in the United States in 2006 and 12.4% of all births in the United States in 2004. See, e.g., Use of progesterone to reduce preterm birth, American College of Obstetricians and Gynecologists Committee Opinion No. 291, Vol. 102, No. 5, November 2003, pages 1115-1116; Hamilton, B. E., Annal Summary of Vital Statistics: 2005, Pediatrics, Vol. 119, No. 2, February 2007, pages 345-360.
It is believed that a preterm birth prior to 32 weeks of gestation represents an extremely high risk of morbidity and mortality. Additionally, a preterm birth between 32 and 36 weeks of gestation has been found to be particularly alarming as having a great number of at risk infants. Preterm delivery accounts for 60-70% of infant mortality, and is a leading cause of health care expenditures in both the perinatal period and throughout life for infant survivors. Recent advances in modern obstetric and neonatal care have led to improved infant survival, however, 55% of newborns with an extremely low birth weight (<1000 g) or delivered very premature (<28 weeks) who survive to middle childhood show evidence of clinically significant cognitive, educational, and behavioral impairment.
Approximately 20%-30% of preterm births are the result of a physician's decision to bring about delivery for maternal or fetal indications. The remainder of preterm deliveries is spontaneous, usually following the onset of premature labor or rupture of the membranes. Several risk factors for preterm labor have been identified including: multi-fetal gestation, maternal stress, systemic and intrauterine infection, race, and socioeconomic status. The Preterm Prediction Study found that a history of prior spontaneous preterm delivery was a strong predictor of subsequent preterm delivery with a prior delivery at 23-27 weeks giving rise to an 11-fold increase in the risk. Unfortunately, however, risk assessment methods using only historical risk factors have an unacceptably low sensitivity and poor predictive value. Supplementing historical-based risk assessment with technology, specifically an ultrasonographic assessment of the cervix, adds improved sensitivity and specificity. Ultrasound identification of cervical shortening is correlated with a logarithmic increase in the risk of preterm delivery. See Iams et al, The length of the cervix and the risk of spontaneous premature delivery, N. Engl. J. Med. 1996; 334: 567-572.
Of the surviving premature infants, many are afflicted with lifelong difficulties such as cerebral palsy, mental retardation, chronic lung disease, hearing and vision deficits, and learning disabilities. The more mature a child is at birth, the more likely he or she is to survive and the less likely he or she is to have related health problems. Premature babies born between 34 and 37 weeks are generally relatively healthy. If a woman goes into labor before 34 weeks, however, the risks of adverse health effects and/or medical complications increase.
It is generally known that the length of a woman's cervix is a good indication of whether a pregnant woman will experience preterm labor and preterm birth. Physicians routinely check the length of a woman's cervix at the first prenatal visit, so that they can monitor changes in cervical length as the pregnancy progresses. If a woman's cervix gets shorter at midpregnancy, it means that the cervix is beginning to efface (thin out), and it is a good indication that the woman is at higher risk for preterm delivery.
Cervical shortening, and to some degree such characteristics as previous preterm birth history, age, ethnicity, body mass index (BMI) and cervical surgery, are conventionally known risk factors related to preterm birth. Data support an inverse relationship between cervical length and preterm delivery. In a prospective study of 2915 women that investigated the relationship between short cervical length and preterm delivery, researchers found that even a small decrease in cervical length between the 24th and 28th weeks of gestation was associated with an increased risk of preterm birth (RR 2.03; 95% CI, 1.28-3.22). See lams et al, The length of the cervix and the risk of spontaneous premature delivery, N. Engl. J. Med. 1996; 334: 567-572. At 24 weeks, when compared with women whose cervical length was above the 75th percentile of normal, women who had a cervical length in the 25th percentile (<3.0 cm) had a relative risk of preterm delivery of 3.79 (95% CI, 2.32-6.19); those in the 10th percentile (<2.6 cm) had a relative risk of 6.19 (95% CI, 3.84-9.97); those in the 5th percentile (<2.2 cm) had a relative risk of 9.49 (95% CI, 5.95 to 15.15); and those in the 1st percentile (<1.3 cm) had a relative risk of 13.99 (95% cm 7.89 to 24.78). Id. Other studies have determined that monitoring cervical length may aid in the identification of women at an increased risk for recurrent preterm birth. See Spong, C., Prediction and prevention of recurrent spontaneous preterm birth, American College of Obstetricians and Gynecologists, Vol. 110, No. 2, Part 1, August 2007, pages 407-408.
There is currently no approved therapy for preventing preterm births in the United States. See Institute of Medicine Report on Preterm Birth, 2006. Existing medical practice for preventive treatments regarding a short cervix early in gestation involves mechanical/surgical treatments. For example, cervical cerclage is a surgical procedure where the cervix is sewn or stitched closed, thus physically preventing the cervix from prematurely shortening or thinning out. The stitches are then removed, typically at about week 37, to allow normal dilation of the cervix during labor. Unfortunately, typical adverse effects associated with cervical cerclage procedures include risk of premature contractions, cervical dystocia (inability of the cervix to dilate normally during labor), cervical infections, and other risks generally associated with surgical procedures. In addition, there is controversy about the effectiveness of cerclage in the treatment of a short cervix. Several recent studies suggest this surgical treatment is no better than placebo. Although cervical length, specifically cervical shortening is known to be correlated to preterm birth, no non-surgical intervention is presently known to be efficacious. See Spong, C., pages 407-408. That is, there is currently no accepted medical treatment for the risk factor for preterm labor and birth known as “short cervix”.
Progesterone administration has been advocated for the prevention of preterm birth in certain women considered to be at high risk, although the primary focus has been on patients with a prior history of preterm birth. The efficacy of vaginally administered progesterone to prevent preterm birth in women at especially high risk of preterm delivery, particularly women experiencing cervical shortening, is far from concrete and is largely unknown. O'Brien et al., for example, have determined that prophylactic treatment with vaginal progesterone gel does not effectively reduce the frequency of recurrent preterm birth in high risk women selected by a history of spontaneous preterm birth. As provided by the Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists in the publication, Use of Progesterone to Reduce Preterm Birth, American College of Obstetricians and Gynecologists Committee Opinion No. 291, Vol. 102, No. 5, November 2003, pages 1115-1116, the ideal progesterone formulation is unknown, however.
The use of progesterone to treat all women at risk for preterm birth does not have unqualified support at present. Several authors have expressed the need for adequately designed, randomized trials in larger populations to identify the ideal progesterone formulation and dosage, and to demonstrate a decline in preterm births before 37 weeks and a reduction in perinatal morbidity and mortality. See, e.g., Dodd et al, Prenatal administration of progesterone for preventing preterm birth, Cochrane Database Syst Rev 2006.
While there is much debate regarding the use of progesterone regarding birth, specifically regarding the period of gestation, there is little, if any, conventional art analyzing effects to neonatal populations based on treatments for preventing preterm birth. Meta-analysis of randomized trials involving women revealed that there may be a reduction in the risk of preterm birth less than 37 weeks and 34 weeks. Dodd, J. M. et al, Prenatal administration of progesterone for preventing preterm birth (Review), The Cochrane collaboration, John Wiley Sons, Ltd, 2006, pages 1-36. Importantly, however, there was no statistically significant difference in the occurrence of perinatal death between women administered progesterone and those administered placebo. Dodd, J. M. et al, pages 4-5. In fact, no differences were reported regarding neonatal outcomes between the placebo and progesterone groups. Dodd, J. M. et al, pages 4-5; Mackenzie, R. et al., Progesterone for the prevention of preterm birth among women at increased risk: A systematic review and meta-analysis of randomized controlled trials, Journal of Obstetrics and Gynecology, 194, 2006, pages 1234-42.
One study provided information regarding pregnancy prolongation and the morbidity of the child. Lam, F. et al., Evaluation of the pregnancy prolongation index (PPI) as a measure of success of obstetric interventions in the prevention of preterm birth and associated morbidities, Journal of Obstetrics and Gynecology, 192, 2005, 2047-54. This study, however, provided no comparative experimental data between treatment groups and control groups. Moreover, this study did not relate to use of progesterone for treatment or prophylaxis of preterm birth. Ultimately, this study was limited to examining neonatal health simply as a function of gestational age at delivery rather than as a consequence of a treating/prophylactic agent.
Thus, there is a need for a method of treating or preventing the onset of preterm labor and resulting preterm birth in pregnant women, particularly for women having a short cervix, without the adverse health effects that are typically associated with currently known methods. Moreover, beyond just focusing on the health of the mother giving birth, there needs to be a strong focus on, and intervention for, improving neonatal outcome. That is, preterm birth is associated with high perinatal morbidity and mortality; and suppression of premature labor has not conventionally been associated with improved infant outcomes. The conventional art does not show any direct health benefits to the neonate. Therefore, there is a need in the art for treatment and/or prophylaxis to improve natal, particularly neonatal, health for births occurring preterm.